Method for treating arrhythmia by using 1,4-bis(4 quinazolinyl) piperazines

ABSTRACT

Certain bis(4-quinazolinyl) piperazines, e.g., 1,4-bis(6,7dimethoxy-4-quinazolinyl)piperazine, are useful as antiarrhythmic agents.

United States Patent Simpson 1 May 20, 1975 METHOD FOR TREATING ARRHYTHMIA BY USING 1,4-BlS(4 QUINAZOLINYL) PIPERAZINES William R. Simpson, Mendham, NJ.

Sandoz-Wander, lnc., E. Hanover, NJ.

Filed: Feb. 20, 1973 Appl. No.: 333,556

Related US. Application Data Continuation-in-part of Ser. No. 241,408, April 5, 1972, abandoned.

Inventor:

Assignee:

US. Cl. 424/251 Int. Cl A61k 27/00 Field of Search 424/251 [56] References Cited UNITED STATES PATENTS 3,594,480 7/1971 Cronin et al 424/250 [57] ABSTRACT Certain bis(4-quinazolinyl) piperazines, e.g., 1,4- bis(6,7-dimethoxy-4-quinazolinyl)piperazine, are useful as anti-arrhythmic agents.

6 Claims, No Drawings METHOD FOR TREATING ARRHYTHMIA BY USING 1,4-BIS(4 QUINAZOLINYL) PIPERAZINES This application is a continuation-in-part of copending U.S. Pat. Application, Ser. No. 241,408 filed Apr. 5, 1972 now abandoned.

This invention relates to the pharmaceutical activity of bis(4-quinazo-linyl)piperazine derivatives. More particularly, this invention concerns the use of 1,4- bis(4-quinazolinyl) piperazines in the treatment of arrhythmia in mammals. The invention also relates to pharmaceutical compositions containing the above compounds as an active ingredient thereof.

The active agents with which this invention is concerned may be represented by the following structural formula:

ll 2 (I) n E N where R, and R each independently represent hydrogen or lower alkoxy i.e., alkoxy having 1 to 4 carbons atoms, e.g., methoxy, ethoxy, isopropoxy and the like, or a pharmaceutically acceptable acid addition salt thereof.

The preferred compound of formula (I) is the compound in which R, and R are both methoxy, namely 1,4-bis (6,7-dimethoxy-4-quinazolinyl)piperazine.

The compounds of formula (1) above are known and may be prepared according to methods disclosed in the literature from known materials, for example as described in Example XIV of U.S. Pat. No. 3,594,480. The present invention contemplates only the novel use of such compounds in pharmaceutical applications, in particular in the treatment of arrhythmia.

As indicated above, the compounds of formula (I) are useful in animals as anti-arrhythmic agents as indicated by polygraph recordings on anesthetized dogs given micrograms per kilogram of oubain every 10 minutes until the appearance of constantly-occurring ventricular ectopic beats following which 0.1 to 10 milligrams per kilogram of the test compound is administered intravenously every two minutes until the arrhythmia reverts to sinus rhythm. The dog is anesthetized with 30 mg/kg i.v., of sodium pentobarbitol and the polygraph recordings are made with a lead II electrocardiogram using pressure transducers connected to the cannulated fermoral artery.

For such usage, the compounds may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs and parenterally as solutions, suspensions, dispersions, emulsions and the like, e.g. a sterile injectable aqueous solution. The compositions may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin and acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastro intestinal tract and thereby provide a sustained action over a longer period. Similarly, oral liquids, e.g., suspensions may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate) wetting agents (lecithin, polyoxyethylene stearate and polyoxy-ethylene sorbitan mono-oleate) and preservatives (ethyl-o-hydroxybenzoate). Capsules may contain the active ingredient alone or admixed with'an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated 'as known in the art. These pharmaceutical preparations may contain up to about percent of the active ingredient in combination with the carrier or adjuvant.

Furthermore, the compounds of formula (I) may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such malate, tartrate, methanesulfonate, cyclohexylsulfamate and the like.

The anti-arrhythmic effective dosage of the compounds of formula (I) employed in the alleviation of arrhythmia may vary depending on the. particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of formula (I) are administered at a daily dosage of from about 3 milligrams to about 300 milligrams per kilogram of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 200milligrams to about 3000 milligrams. Dosage forms suitable for internal use comprise'from about 50 to about 1500 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions, particularly hardfilled capsules and tablets containing from about to 250 milligrams of the active ingredient.

EXAMPLES 1 AND 2 Tablets and Capsules Suitable For Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional tech- 3 4 niques and are useful in treating arrhythmia at a dose What is claimed is: of one tablet or capsule 2 to 4 times a day. l. A method for treating arrhythmia, which comprises administering to a mammal in need of said treatment an anti-arrhythmic effective amount of a comlngred'em weigh (mg) 5 pound of the formula:

tablet capsule l,4-bis( 6,7-dimethoxy-4-quinazol R linyl) piperazine 150 150 1 tragacanth l l lactose 297.5 150 corn starch 25 [0 N talcum l R 1 magnesium stearate 2.5 Total 500 mg. 300 mg. [N] In a similar manner, tablets and capsules may be pre- X pared using l,4-bis(4-quinazolinyl)piperazine or 1,4- R bis(7methoxy-4-quinazolinyl)-piperazine as the active 2 ingredient in place of the l,4-bis(6,7-dimethoxy-4- quinazolinyl)piperazine above. Rl

EXAMPLES 3 AND 4 h d where R and R each independently represent y ro- Stenle Suspenslon and Oral Llquld gen or lower alkoxy or a pharmaceutically acceptable uspenslon acid addition salt thereof.

The following pharmaceutical compositions are for- 2. A method according to claim 1 wherein the commulated with the indicated amount of the active agent pound is administered at a daily dosage of .from about usin conventional techni ues. The in'ectable sus en- 200 milli rams to about 3000 milligrams.

8 q .l P g sion and the oral li uid sus ension re resent formula- 3. A method according to claim 1 where in the comq p p a u tions useful as unit doses and ma be administered in ound is administered in a unit dosage form comprlsmg the treatment of arrhythmia. The injectable suspension said compound to the extent of from about milliis suitable for administration once or twice a day 30 grams to about 1500 milligrams per unit dosage.

whereas the oral liquid suspension is suitable adminis- 4. A method according to claim 1 in which the comtered 2 to 4 times per day for this purpose. pound is l,4-bis(6,7-dimethoxy-4-quinazolinyl)pipera- Ingredients Weight (mg) injectable suspension liquid suspension l,4-bis( 6,7-dimethoxy-4- quinazolinyl)piperazine 200 200 sodium carboxy methyl cellulose U.S.P. 1.25 12.5 methyl cellulose 0.4 polyvinylpyrrolidone 5 lecithin 3 benzyl alcohol 0.01 magnesium aluminum silicate 47.5 flavor q.s. color q.s. mathyl paraben. U.S.P. 4.5 propyl paraben. U.S.P. l.0 polysorbate 80 (e.g. Tween 80), USP 5 sorbitol solution, 70%, USP 2,500 buffer agent to adjust pH for desired stability q.s. q.s. water for injection. q.s. to 5 ml.

' q.s. to 1 ml.

In a similar manner, injectable suspensions and liquid zine. suspension may be prepared using l,4-bis(4- 5. A method according to claim 1 in which the comquinazolinyl)piperazine or l,4-bis(7- pound is l,4-bis(4-quinazolinyl)piperazine. methoxy-4-quinazolinyl)piperazine as the active ingre- 6. A method according to claim 1 in which the comdient in place of the 1,4-bis (6,7-dimethoxy-4- pound is l,4-bis(7-methoxy-4-quinazolinyl)piperazine. quinazolinyl)piperazine above. 

1. A METHOD FOR TREATING ARRHYTHMIA WHICH COMPRISES ADMINISTERING TO A MAMMAL IN NEED OF SAID TREATMENT AN ANTIARRTHYMIC EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
 2. A method according to claim 1 wherein the compound is administered at a daily dosage of from about 200 milligrams to about 3000 milligrams.
 3. A method according to claim 1 where in the compound is administered in a unit dosage form comprising said compound to the extent of from about 50 milligrams to about 1500 milligrams per unit dosage.
 4. A method according to claim 1 in which the compound is 1,4-bis(6,7-dimethoxy-4-quinazolinyl)piperazine.
 5. A method according to claim 1 in which the compound is 1,4-bis(4-quinazolinyl)piperazine.
 6. A method according to claim 1 in which the compound is 1,4-bis(7-methoxy-4-quinazolinyl)piperazine. 